Progesterone (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation), and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. Progesterone can be used alone, or in combination with estrogenic agents, to provide a hormonal state in women through hypothalamic, pituitarian, and some endometrial effects to enable contraception and some non-contraception indications, such as endometriosis, regular menstrual cycles, improvement in acne, dysmenorrhea and premenstrual symptoms such as dysphoric disorder, also known as PMDD, polycystic ovarian syndrome (PCOS), perimenopause, hirsutism (undesired body or facial hair growth). Although quite effective, oral hormonal contraceptive use is generally characterized by poor adherence and relatively high discontinuation. The primary objective of contraception is to achieve an anovulatory state with acceptable menstrual cycle characteristics and side effect profile.
Progesterone's role in contraception is primarily through prevention of ovulation by suppressing follicle stimulating hormone (FSH) and luteinizing hormone (LH), preventing implantation of fertilized ovum by suppressing endometrium development, and to thicken cervical mucus making sperm penetration difficult. Synthetic or natural estrogen, if used in combination with a progestogen, provides better cycle control and prevents estrogen deficiency due to decreased secretion of endogenous estrogen from the follicle. Estrogen inhibits FSH release from the anterior pituitary to prevent selection of dominant follicle, to provide stability to endometrium, to decrease rate of breakthrough bleeding, to thin cervical mucus, and to increase expression of progesterone receptors.
Progestogen only pills (POPs) for oral contraception are typically started on days 1 to 5 of the menstrual cycle and particularly suited for women who are smokers and over 35 years old, overweight or obese, over the age of 45, diabetic, prone to chloasmia, intolerant to estrogen, nursing mothers, prone to migraine with aura, and have hypertension. Currently, combination (progestogen plus estrogen) oral contraceptive (COC) pills are most preferred due to reportedly more reliable efficacy if used as directed, they have better cycle control and are more forgiving with respect to missed dose related safety margins associated with contraception failure. In contrast, commercially available progestogen-only oral contraceptives must be taken at nearly the exact same time every day to reduce the risk of contraceptive failure with “missed dose” related safety margin of only a few hours.
Orally-administered progesterone undergoes several successive metabolic steps in the gut, intestinal wall, and liver. The first step is the contact with intestine bacteria which has 5α reductase activity, then with the intestinal wall, predominantly the upper gastro-intestinal wall which has 5α-reductase activity and also initiates conjugation of steroids with glucuronic acid. The second step is the contact with liver enzymes after circulation in the portal vascular systems. Liver cells in women express mainly 5α-reductase, 3α and 20α-hydroxylase activities. 3α-OH-5α-pregnan-20-one is known as allopregnanolone and 3α-OH-5α-pregnan-20-one is known as pregnanolone. Both of the metabolites can be collectively addressed as “pregnane” metabolites. Pregnane metabolites are neurosteroids and are active agonists on the Gamma Amino Butyric Acid-A (GABAA) receptor unlike progesterone per se. High doses of GABAA receptor agonists such as pregnane metabolites induce dizziness, sedation, hypnosis, and anxiolysis, and are antiepileptic. Therefore, reduced level of pregnane metabolites provides acceptable progesterone therapy without significant adverse events such as sedation, dizziness and hypnosis.
Synthetic combination oral contraceptives also have higher cardiovascular risk such as ischemic stroke, venous thromboembolism (VTE), myocardial infarction, arterial hypertension. It has been suggested that COC's may contribute to the risk of breast cancer in a woman. These side effects and increased risks are associated with, progestin and/or estrogen, its relative doses, or the recommended dosing regimen. Overall, the lack of high selectivity/specificity of synthetic progestins to progesterone receptors, estrogenic action and/or anti-estrogenic action, antimineralocorticoid activity, androgenic action and/or anti androgenic action, appear to be associated with varying intensities of the side effects. Unlike some synthetic progestins like gestodene, levonorgesterol, etc. natural progesterone has low binding affinities to human sex hormone binding globulin (SHBG). Progestins having antiandrogenicity effects could result in loss of libido and compromised sexual health. This can be particularly true when they are combined with ethinyl estradiol. This effect is primarily due to androgen insufficiency through direct inhibition of androgen production in the ovaries and by a marked increase in the hepatic synthesis of SHBG, which is known to bind to circulating testosterone making it less bioavailable. Increases in SHBG values as high as 400% have been reported in users of ethinyl estradiol based combination oral contraception as compared to women who never used combination oral contraception.
The delivery of progesterone via oral route in a suitable way for contraception and non-contraception use still remains a challenge given its extensive metabolism to neurosteroids. With this in mind, research continues to develop natural progesterone oral dosage forms that can be used to effectively provide contraceptive and non-contraceptive activity without having the negative side-effects associated with synthetic progestins.
Currently, ethinyl estradiol (EE) is the most utilized estrogen in a combination oral pill with androgenic progestin such as levonorgestrel (e.g. Lybrel®) or anti-androgenic progestin such as drosperinone (e.g. Yaz® and Yasmin®). Estrone producing bioidentical 17-estradiol or its ester prodrug, estradiol valerate, is also commonly combined with progestins in combination oral pills, e.g. Natazia® with dienogest/estradiol valerate, Zoely® with nomegestrol acetate with 17-estradiol), and presumably have less hepatic effect compared to EE containing combinations. However, their use in combination may provide cycle management challenges that need to be offset by proper choice of progestin, balance of progestin to estrogen, and multitude of dosing regimens for acceptable cycle control. A combination of estradiol and norethindrone acetate is available for non-contraception treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis, and treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause.
Currently, the only known POP contraceptive pills are in the form of anti-androgenic desogestrel sold outside the U.S. as Cerazette® with a 12 hour “missed dose” related safety margin to prevent contraception failure and androgenic norethindrone sold as Micronor® in US with a 3 hour “missed dose” related safety margin for contraception failure, or androgenic levonorgestrel sold as Microlut®. Most available combination pill contain anti-androgenic progestins such as drospirenone and dinogest, or androgenic levogersterol, and norethindrone. Normegesterol acetate (NOMAC), a non-androgenic and non-anti-androgenic progestin with a long half-life is devoid of anti-mineralocorticoid activity, which is critical to manage metabolic side effects. It is also known that progestins with stronger androgenic activity have a stronger negative impact on lipid metabolism.
The sub-optimal half-life of synthetic androgenic or antiandrogenic progestins present challenges w.r.t. to pill amenorrhea due to very long half-life in women who desire to bleed at least few times a year to ascertain their reproductive health and time to reversibility (e.g. ˜7 days with drosperinone-containg pills) in case of contraception cessation and wanting to become pregnant without risking progestin effects on the fetus. While shorter half progestins have favorable pill amenorrhea and reversibility profile they also result in a shorter missed dose safety margin of 3 hr and lower efficacy due to lower anovulation rates (˜50%) such as with norethindrone.